Pharm 202 Computer Aided Drug Design

Phil Bourne bourne@sdsc.edu http://www.sdsc.edu/pb -> Courses -> Pharm 202

Several slides are taken from UC Berkley Chem 195

Perspective
Principles of drug discovery (brief) Computer driven drug discovery Data driven drug discovery Modern target identification and selection Modern lead identification

Overall strong structural bioinformatics emphasis

What is a drug?
Defined composition with a pharmacological effect Regulated by the Food and Drug Administration (FDA) What is the process of Drug Discovery and Development?

Drugs and the Discovery Process

Small Molecules
Natural products
fermentation broths plant extracts animal fluids (e.g., snake venoms)

Synthetic Medicinal Chemicals

Project medicinal chemistry derived Combinatorial chemistry derived

Biologicals
Natural products (isolation) Recombinant products Chimeric or novel recombinant products

Discovery vs. Development

Discovery includes: Concept, mechanism, assay, screening, hit identification, lead demonstration, lead optimization Discovery also includes In Vivo proof of concept in animals and concomitant demonstration of a therapeutic index Development begins when the decision is made to put a molecule into phase I clinical trials

Discovery and Development

The time from conception to approval of a new drug is typically 10-15 years The vast majority of molecules fail along the way The estimated cost to bring to market a successful drug is now $800 million!! (Dimasi, 2000)

Drug Discovery Processes Today

Physiological Hypothesis

Molecular Biological Hypothesis (Genomics)

Primary Assays Biochemical Cellular Pharmacological Physiological

+
Chemical Hypothesis Sources of Molecules Natural Products Synthetic Chemicals Combichem Biologicals

Screening

Initial Hit Compounds

Drug Discovery Processes - II

Secondary Evaluation - Mechanism Of Action - Dose Response Hit to Lead Chemistry - physical properties -in vitro metabolism

Initial Hit Compounds

Initial Synthetic Evaluation - analytics - first analogs

First In Vivo Tests - PK, efficacy, toxicity

Drug Discovery Processes - III

Lead Optimization Potency Selectivity Physical Properties PK Metabolism Oral Bioavailability Synthetic Ease Scalability Pharmacology Multiple In Vivo Models Chronic Dosing Preliminary Tox

Development Candidate (and Backups)

Drug Discovery Disciplines

Medicine Physiology/pathology Pharmacology Molecular/cellular biology Automation/robotics Medicinal, analytical,and combinatorial chemistry Structural and computational chemistries Bioinformatics

Drug Discovery Program Rationales

Unmet Medical Need Me Too! - Market - ($$$s) Drugs in search of indications
Side-effects often lead to new indications

Indications in search of drugs

Mechanism based, hypothesis driven, reductionism

Serendipity and Drug Discovery

Often molecules are discovered/synthesized for one indication and then turn out to be useful for others
Tamoxifen (birth control and cancer) Viagra (hypertension and erectile dysfunction) Salvarsan (Sleeping sickness and syphilis) Interferon-E (hairy cell leukemia and Hepatitis C)

Issues in Drug Discovery

Hits and Leads - Is it a Druggable target? Resistance Pharmacodynamics Delivery - oral and otherwise Metabolism Solubility, toxicity Patentability

A Little History of Computer Aided Drug Design

1960s - Viz - review the target - drug interaction 1980s- Automation - high trhoughput target/drug selection 1980s- Databases (information technology) - combinatorial libraries 1980s- Fast computers - docking 1990s- Fast computers - genome assembly - genomic based target selection 2000s- Vast information handling - pharmacogenomics

From the Computer Perspective

Progress
About the computer industry If the automobile industry had made as much progress in the past fifty years, a car today would cost a hundredth of a cent and go faster than the speed of light.
Ray Kurzweil, The Age of Spiritual Machines

Growth of pixel fill rates

1200 1000

F ill ra te , M p ix e ls /s

800

600

SGI

PC cards

400

200

0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

* Not counting custom hardware or special configurations

Fill rates recently growing by x2 every year

Data source: Product literature

Comparing Growth Rates

40 Processor performance growth 35 30 Increase factor 25 20 15 10 5 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Memory bus speed growth Pixel fill rate growth

From the Target Perspective

Bioinformatics - A Revolution
Biological Experiment Data Information Knowledge Discovery

Collect Complexity Higher-life Organ Cellular Sub-cellular Assembly Structure Sequence 90

(C) Copyright Phil Bourne 1998

Characterize

Compare

Model Data 1000

Infer Technology

10
Brain Mapping

100

100000 Computing Power

Cardiac Modeling Model Metaboloic Pathway of E.coli

106 Virus Structure Human Genome Project ESTs

102 Neuronal Modeling Ribosome Genetic Circuits E.Coli C.Elegans Yeast Genome Genome Genome Gene Chips

# People/Web Site

1 Small Genome/Mo. Human Genome

95 Year

00

05

Sequencing Technology

The Accumulation of Knowledge

This molecular scene for cAMP dependant protein kinase (PKA) depicts years of collective knowledge. Traditionally structure determination has been functional driven As we shall see it is becoming genomically driven

History

History
Strong sense of community ownership We are the current custodians The community watches our every move The community itself is changing

Status - Numbers and Complexity

(a) myoglobin (b) hemoglobin (c) lysozyme (d) transfer RNA (e) antibodies (f) viruses (g) actin (h) the nucleosome (i) myosin (j) ribosome

Courtesy of David Goodsell, TSRI

The Structural Genomics Pipeline (X-ray Crystallography)

Basic Steps
Crystallomics Isolation, Target Expression, Data Selection Purification, Collection Crystallization Structure Solution Structure Refinement Functional Annotation

Publish

Bioinformatics Distant homologs Domain recognition

Automation Bioinformatics Empirical rules

Automation Better sources

Software integration Decision Support MAD Phasing Automated fitting

Anticipated Developments

No? Bioinformatics Alignments Protein-protein interactions Protein-ligand interactions Motif recognition

structure info

sequence info

Protein sequences
Prediction of : signal peptides (SignalP, PSORT) transmembrane (TMHMM, PSORT) coiled coils (COILS) low complexity regions (SEG)

SCOP, PDB

NR, PFAM

Building FOLDLIB: -----------------------------------PDB chains SCOP domains PDP domains CE matches PDB vs. SCOP ----------------------------------90% sequence non-identical minimum size 25 aa coverage (90%, gaps <30, ends<30)

Structural assignment of domains by PSI-BLAST on FOLDLIB-PRF

Only sequences w/out A-prediction

Structural assignment of domains by 123D on FOLDLIB-PRF Create PSI-BLAST profiles for FOLDLIB vs. NR
Only sequences w/out A-prediction

Functional assignment by PFAM, NR, PSIPred assignments

FOLDLIB-PRF Domain location prediction by sequence Store assigned regions in the DB

The Genome Annotation Pipeline

Example - http://arabidopsis.sdsc.edu

From the Drug Perspective

Combinatorial Libraries
Thousands of variations to a fixed template Good libraries span large areas of chemical and conformational space - molecular diversity Diversity in - steric, electrostatic, hydrophobic interactions... Desire to be as broad as Merck compounds from random screening Computer aided library design is in its infancy

Blaney and Martin - Curr. Op. In Chem. Biol. (1997) 1:54-59

Statement the ector, Subcommittee on abor,

S, efore the ouse ropriations S, ucation hurs ay, ebruary ,